Peptidoglycan is a cross-linked carbohydrate polymer that forms layers around bacterial cell membranes. One of its primary functions is to protect bacterial cells from lysis due to fluctuations in internal osmotic pressure. The machinery for peptidoglycan biosynthesis is highly conserved in both Gram-negative and Gram-positive bacteria, and each of the enzymes involved in the pathway is a potential target for antibiotic chemotherapy. Walsh, C. T., Antibiotics: Actions, Origins, Resistance; ASM Press: Washington, D.C., 2003. Wong, K. K., Pompliano, D. L., Adv. Exp. Med. Biol. 1998, 456, 197-217; El Zoeiby, A., et al., Mol. Microbiol., 2003, 47, 1-12; Salmond, G. P., et al., J. Bacteriol. 1980, 144, 438-440; Ikeda, M.; Wachi, M., et al., Nucleic Acids Res. 1990, 18, 4014; Mengin-Lecreulx, D., et al., J. Bacteriol. 1991, 173, 4625-4636; Bupp, K., et al., J. Bacteriol. 1993, 175, 1841-1843; Men, H., Park, P., Ge, M., Walker, S. J. Am. Chem. Soc., 1998, 120, 2484-2485; Chen, L., Men, H., Ha, S., Ye, X.-Y., Brunner, L., Hu, Y., Walker, S. Biochemistry 2002, 41, 6824-6833; Ha, S., Walker, D., Shi, Y., Walker, S., Protein Sci. 2000, 9, 1045-1052.
MurG is a glycosyltransferase that transfers GlcNAc from UDP to the C4 hydroxyl of an N-acetyl muramic acid peptide anchored to the cytoplasmic surface of a bacterial cell membrane. Inhibitors of MurG are expected to be useful as antibiotics. However, despite considerable effort, it has generally been difficult to design good inhibitors of glycosyltransferases. Wang, R., et al., Bioorg. Med. Chem. 1997, 5, 661-672; Qian, X., et al., Carbohydr. Chem. Biol. 2000, 3, 293-312; Saotome, C., et al., Biol. 2001, 8, 1061-1070; Compain, P., et al., Med. Chem. 2001, 9, 3077-3092.; Compain, P., et al., Curr. Top. Med. Chem. 2003, 3, 541-560; Hu, Y., Chen, L., Ha, S., Gross, B., Falcone, B., Walker, D., Mokhtarzadeh, M., Walker, S. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 845-849. High-throughput screening would provide for the identification of glycosyltransferase inhibitors.